Pro12Ala polymorphism in peroxisome proliferator-activated receptorγ2 (PPARγ2):: beta-cell function and insulin sensitivity

Background and objective: The peroxisome proliferator-activated receptor isoform gamma (PPAR gamma) is a key regulator in lipid and glucose homoeostasis. A common polymorphism (Pro12Ala in PPAR gamma (2), prevalence ca. 25%) was shown to be associated with a decreased risk of type 2 diabetes. Generally, both beta-cell dysfunction and insulin resistance contribute to the development of type 2 diabetes. Therefore, the aim of the present study was to assess the mechanism by which the Ala allele of this polymorphism contributes to the reduced risk for type 2 diabetes. Patients and methods: We studied 51 subjects without (Pro/ Pro) and 26 subjects with this polymorphisms (X/Ala) (both groups non-diabetic) by a modified hyperglycaemic clamp which permitted determination of both insulin secretion (in response to glucose, GLP-1 and arginine) and insulin sensitivity. Results: None of the various phases of insulin secretion was significantly different between the 2 genotype groups (all p values > 0.13). In contrast, insulin sensitivity was significantly greater in X/Ala (0.19+/-0.03 U) compared to Pro/Pro (0.14+/-0.01U, p = 0.04). In a two-dimensional assessment of insulin sensitivity and secretion, the homozygous alanine carriers appeared to have the most favourable constellation. Conclusion: These simultaneously obtained data for insulin secretion and sensitivity strongly suggest that the mechanism by which the Ala allele contributes to a risle reduction for type 2 diabetes most likely involves an increase in insulin sensitivity.